Discovery of fragments that target key interactions in the signal recognition particle (SRP) as potential leads for a new class of antibiotics

Camilla Faoro; Lorna Wilkinson-White; Ann H Kwan; Sandro F Ataide

doi:10.1371/journal.pone.0200387

Discovery of fragments that target key interactions in the signal recognition particle (SRP) as potential leads for a new class of antibiotics

PLoS One. 2018 Jul 25;13(7):e0200387. doi: 10.1371/journal.pone.0200387. eCollection 2018.

Authors

Camilla Faoro¹, Lorna Wilkinson-White², Ann H Kwan¹, Sandro F Ataide¹

Affiliations

¹ School of Life and Environmental Sciences, The University of Sydney, Sydney, Australia.
² Sydney Analytical Core Facility, The University of Sydney, Sydney, Australia.

Abstract

Given the increasing incidence of antibiotic resistance, antibiotics that employ new strategies are urgently needed. Bacterial survival is dependent on proper function of the signal recognition particle (SRP) and its receptor (FtsY). A unique set of interactions in FtsY:SRP-RNA represents a promising candidate for new antibiotic development as no antibiotic targets this complex and these interactions are functionally replaced by protein:protein interactions in eukaryotes. We used a Fragment Based Drug Design (FBDD) approach to search for new compounds that can bind FtsY, and have identified three lead fragments. In vitro and in vivo analyses have shown that despite a high micromolar binding affinity, one fragment has some antimicrobial properties. X-ray structures of E. coli FtsY:fragments reveal the fragments bind in the targeted RNA interaction site. Our results show that FBDD is a suitable approach for targeting FtsY:SRP-RNA for antibiotic development and opens the possibility of targeting protein:RNA interactions in general.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acinetobacter baumannii
Anti-Bacterial Agents / pharmacology*
Bacterial Proteins / metabolism*
Binding Sites
Drug Design
Drug Resistance, Bacterial / drug effects
Drug Resistance, Bacterial / physiology
Escherichia coli
Escherichia coli Proteins / metabolism
Nuclear Magnetic Resonance, Biomolecular
Proton Magnetic Resonance Spectroscopy
Receptors, Cytoplasmic and Nuclear / metabolism*
Signal Recognition Particle / metabolism*
Surface Plasmon Resonance

Substances

Anti-Bacterial Agents
Bacterial Proteins
Escherichia coli Proteins
FtsY protein, Bacteria
Receptors, Cytoplasmic and Nuclear
Signal Recognition Particle

Grants and funding

This work was supported by internal University funding to SFA and AK, ANSTO NDF grant 5132 to SFA and AK as well as ARC LIEF grant LE160100047 to AK. We are grateful for financial contributions from the University of Sydney, including from the Faculties of Science and Medicine and School of Life and Environmental Sciences for support of the NMR and X-ray crystallography facilities that were used in this work. https://sydney.edu.au/; http://www.ansto.gov.au/; http://www.arc.gov.au/.